Prognostic factors for progression in atypical meningioma Shakir I. Shakir, Luis Souhami, Kevin Petrecca, Jose João Mansure, Khushdeep Singh, Valerie Panet-Raymond, George Shenouda, Amal A. Al-Odaini, Bassam Abdulkarim, Marie-Christine Guiot Journal of Neurosurgery, 2018 OBJECTIVEThe optimal adjuvant management for atypical meningiomas remains controversial. The aim of this study was to review long-term outcomes to identify potential prognostic factors for disease progression.METHODSFrom August 1992 to August 2013, 70 patients with atypical meningioma were treated at the authors’ institution. Pathology revision was performed based on WHO 2007 criteria. Patients with multiple tumors, neurofibromatosis Type 2, or inadequate imaging follow-up were not eligible. The authors performed pre- and postoperative serial measurements of tumor volume from MRI. Age, sex, tumor location, bone involvement, brain invasion, mitotic figures, preoperative disease volume, extent of resection, tumor growth rates, use of adjuvant postoperative radiation therapy (PORT), and residual tumor volume at the time of radiation therapy (RT) were assessed by univariate and multivariate analysis to determine their potential impact on disease progression.RESULTSForty patients (57%) underwent gross-total resection (GTR) and 30 (43%) underwent subtotal resection (STR). PORT was delivered to 12 patients (30%) with a GTR and in only 4 (13%) with an STR. The 5-year progression-free survival (PFS) rate for patients in the GTR group with or without PORT was 100% and 54.1%, respectively (p = 0.0058). PFS for patients in the STR group with or without PORT was 75% and 0%, respectively (p = 0.0026). On multivariate analysis, STR and PORT were the only independent significant prognostic factors for disease progression with hazard ratios of 5.4873 (95% CI 2.19–13.72, p = 0.0003) and 0.0464 (95% CI 0.0059–0.364, p = 0.0035), respectively. Based on Youden’s index statistic, a cutoff residual tumor volume of more than 8.76 cm3 at the time of RT was associated with worse PFS (13.6% vs 56%, p = 0.0079). Before receiving RT, the median relative and absolute growth rates and tumor doubling time for patients were 124.2%/year, 4.8 cm3/year, and 1.67 years, respectively. These indices changed after RT to 0.245%/year, −0.09 cm3/year, and −0.005 year, respectively (p < 0.05).CONCLUSIONSIn atypical meningioma, the use of PORT is associated with improved PFS even in patients who undergo GTR. Patients with residual tumor volume larger than 8.76 cm3 have an increased risk of disease progression and should be considered for early RT.
Cyclin D1 cooperates with p21 to regulate TGFβ-mediated breast cancer cell migration and tumor local invasion Meiou Dai, Amal A Al-Odaini, Nadège Fils-Aimé, Manuel A Villatoro, Jimin Guo, Ani Arakelian, Shafaat A Rabbani, Suhad Ali, Jean Jacques Lebrun Breast Cancer Research, 2013 INTRODUCTION: Deregulation of the cell cycle machinery is often found in human cancers. Modulations in the cell cycle regulator function and expression result not only in proliferative advantages, but also lead to tumor progression and invasiveness of the cancer. In particular, cyclin D1 and p21 are often over-expressed in human cancers, correlating with high tumor grade, poor prognosis and increased metastasis. This prompted us to investigate the role of the cyclin D1/p21 signaling axis downstream of transforming growth factor beta (TGFβ) in breast cancer progression. METHODS: Cyclins mRNA and protein expressions were assessed by quantitative real-time PCR and Western blot in triple negative breast cancer cell lines. Co-localization and interaction between cyclin D1 and p21 were performed by immunocytochemistry and co-immunoprecipitation, respectively. Cell migration was assessed by wound healing and quantitative time-lapse imaging assays. In addition, the effects of cyclin D1 on cellular structure and actin organization were examined by staining with F-actin marker phalloidin and mesenchymal intermediate filament vimentin. Finally, a mammary fat pad xenograft mouse model was used to assess mammary tumor growth and local invasion. RESULTS: We found TGFβ to specifically up-regulate the expression of cyclin D1 in triple negative breast cancer cells. Induction of cyclin D1 is also required for TGFβ-mediated cell migration. Suppression of cyclin D1 expression not only resulted in a rounded and epithelial-like phenotype, but also prevented TGFβ-induced vimentin and F-actin co-localization at the cell edge as well as invadopodia formation. Furthermore, TGFβ promoted the nuclear co-localization and physical interaction between cyclin D1 and p21. The co-expression of cyclin D1 and p21 proteins are required for the initial steps of tumor development, as double knockdown of these two molecules prevented primary tumor formation in a Xenograft mouse model. Moreover, the in vivo studies indicated that locally advanced features of the invasive tumors, including skeletal muscle, mammary fat pad and lymphovascular invasion, as well as ulcerated skin, were attenuated in the absence of cyclin D1 and p21. CONCLUSIONS: Thus, our findings highlight the cyclin D1/p21 signaling axis as a critical regulator of TGFβ-mediated tumor growth initiation and local tumor cell invasion, both in vitro and in vivo.
A novel function for p21Cip1 and acetyltransferase p/CAF as critical transcriptional regulators of TGFβ-mediated breast cancer cell migration and invasion Meiou Dai, Amal A Al-Odaini, Ani Arakelian, Shafaat A Rabbani, Suhad Ali, Jean-Jacques Lebrun Breast Cancer Research, 2012 INTRODUCTION: Tumor cell migration and invasion are critical initiation steps in the process of breast cancer metastasis, the primary cause of breast cancer morbidity and death. Here we investigated the role of p21Cip1 (p21), a member of the core cell cycle machinery, in transforming growth factor-beta (TGFβ)-mediated breast cancer cell migration and invasion. METHODS: A mammary fat pad xenograft mouse model was used to assess the mammary tumor growth and local invasion. The triple negative human breast cancer cell lines MDA-MB231 and its sub-progenies SCP2 and SCP25, SUM159PT, SUM149PT, SUM229PE and SUM1315MO2 were treated with 5 ng/ml TGFβ and the protein expression levels were measured by Western blot. Cell migration and invasion were examined using the scratch/wound healing and Transwell assay. TGFβ transcriptional activity was measured by a TGFβ/Smad reporter construct (CAGA12-luc) using luciferase assay. q-PCR was used for assessing TGFβ downstream target genes. The interactions among p21, p/CAF and Smad3 were performed by co-immunoprecipitation. In addition, Smad3 on DNA binding ability was measured by DNA immunoprecipitation using biotinylated Smad binding element DNA probes. Finally, the association among active TGFβ/Smad signaling, p21 and p/CAF with lymph node metastasis was examined by immunohistochemistry in tissue microarray containing 50 invasive ductal breast tumors, 25 of which are lymph node positive. RESULTS: We found p21 expression to correlate with poor overall and distant metastasis free survival in breast cancer patients. Furthermore, using xenograft animal models and in vitro studies, we found p21 to be essential for tumor cell invasion. The invasive effects of p21 were found to correlate with Smad3, and p/CAF interaction downstream of TGFβ. p21 and p/CAF regulates TGFβ-mediated transcription of pro-metastatic genes by controlling Smad3 acetylation, DNA binding and transcriptional activity. In addition, we found that active TGFβ/Smad signaling correlates with high p21 and p/CAF expression levels and lymph node involvement using tissue microarrays from breast cancer patients. CONCLUSIONS: Together these results highlight an important role for p21 and p/CAF in promoting breast cancer cell migration and invasion at the transcriptional level and may open new avenues for breast cancer therapy.
